JP4883837B2 - A novel ion-exchange porous resin for solid-phase extraction and chromatography - Google Patents
A novel ion-exchange porous resin for solid-phase extraction and chromatography Download PDFInfo
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- JP4883837B2 JP4883837B2 JP2000553484A JP2000553484A JP4883837B2 JP 4883837 B2 JP4883837 B2 JP 4883837B2 JP 2000553484 A JP2000553484 A JP 2000553484A JP 2000553484 A JP2000553484 A JP 2000553484A JP 4883837 B2 JP4883837 B2 JP 4883837B2
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- 0 CI(CIC(*)c1ccccc1)I Chemical compound CI(CIC(*)c1ccccc1)I 0.000 description 2
- RDOAUPPSCNSYPM-UHFFFAOYSA-N C1C=CN=CC1 Chemical compound C1C=CN=CC1 RDOAUPPSCNSYPM-UHFFFAOYSA-N 0.000 description 1
- ZESBECXBDGBDBS-UHFFFAOYSA-N C=[I]CCc1ccc(C(CI)I)cc1 Chemical compound C=[I]CCc1ccc(C(CI)I)cc1 ZESBECXBDGBDBS-UHFFFAOYSA-N 0.000 description 1
- DRYGQJLGBRJOIW-UHFFFAOYSA-N CC(c1ccccc1)[I](I)I Chemical compound CC(c1ccccc1)[I](I)I DRYGQJLGBRJOIW-UHFFFAOYSA-N 0.000 description 1
- ZWJDBRSPJWBXMF-UHFFFAOYSA-N IC(c1ccccc1)/[I]=C\I Chemical compound IC(c1ccccc1)/[I]=C\I ZWJDBRSPJWBXMF-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
【０００１】
発明の分野
本発明は、少なくとも１つの疎水性成分、少なくとも１つの親水性成分及び少なくとも１つのイオン交換官能基を含有する固相抽出及びクロマトグラフィー用の新規な多孔質樹脂に関する。
発明の背景
固相抽出（ＳＰＥ）は、例えば、分析試料の予備濃縮及び浄化のために、種々の化学物質の精製のために、また水溶液から毒性又は有用な物質を除去するために広く使用されるクロマトグラフ技術である。ＳＰＥは適当な樹脂を含有するカラム又はカートリッジを用いて一般に実施される。ＳＰＥ法は疎水機構、イオン交換、キレート化機構、収着機構及びその他の機構により検体と相互作用して、流体に検体を結合させ、そして流体から検体を分離できる吸収剤を用いて発展してきた。ＳＰＥの用途に応じて、異なる吸収剤が求められるため、特殊な選択性を持つ新規な特性の吸収剤が必要である。
発明の概要
本発明の目的は優れた湿潤性を示す固相抽出及びクロマトグラフィー用の多孔質樹脂として使用できる化合物を提供することである。
【０００２】
本発明の他の目的は特殊な選択性を有する多孔質樹脂化合物を提供することである。
本発明の他の目的は検体を選択的に捕獲でき、そして検体が保持されないで通過するのを妨害できる多孔質樹脂化合物を提供することである。
【０００３】
本発明の他の目的はイオン交換官能基、疎水性成分及び親水性極性成分を有する多孔質樹脂化合物を提供することである。
本発明の他の目的は溶液から溶質を単離又は除去するために本発明の新規な多孔質樹脂を利用することである。
【０００４】
本発明の更に他の目的は溶液中の溶質の量を分析により決定するために本発明の新規な多孔質樹脂を利用することである。
１つの態様において、本発明は
化学式：
【０００５】
【化６】
の化合物及びその塩を特徴とし、
但し、Ａ、Ｂ及びＣの順番はランダム、ブロック、又はランダム及びブロックの組合せであり；
但し、
【０００７】
【化７】
但し、Ａは
【０００９】
【化８】
から成る群から選ばれ、
但し、Ｂは
【００１１】
【化９】
から成る群から選ばれ、
但し、ＣはＡ又は修正されたＡであり、ここで、修正されたＡは
【００１３】
【化１０】
から成る群から選ばれ、そして
ここで、ＸはＳＯ3Ｈ、ＣＨ2ＣＯ2Ｈ、ＣＨ2ＣＨ（ＣＯ2Ｈ）2、ＣＯ2Ｈ、ＰＯ3Ｈ2、ＰＯ2Ｈ2、ＣＨ2ＰＯ3Ｈ2、ＣＨ2Ｃｌ、ＣＨ2ＮＨ2、ＣＨ2Ｎ［（ＣＨ2）yＣＨ3］2（但しｙは０〜１８の整数である）、ＣＨ2Ｎ+［（ＣＨ2）y=ＣＨ3］3Ｄ-（但しｙ＝は０〜１８の整数そしてＤ-はアニオンである）、ＳＯ2ＮＨＲ（但しＲはポリエチレンイミンである）、及びＣＨ2ＮＨＲ（但しＲはポリエチレンイミンである）から成る群から選ばれる。
【００１５】
本発明の他の態様は少なくとも１つの疎水性単量体と少なくとも１つの親水性単量体を共重合させて共重合体を生成し、そして上記共重合体をスルホン化反応させて、少なくとも１つのイオン交換官能基、少なくとも１つの親水性成分、及び少なくとも１つの疎水性成分を含むスルホン化共重合体を生成することにより得られる多孔質樹脂である。
【００１６】
好ましい態様において、上記疎水性単量体はジビニルベンゼンであり、上記親水性単量体はＮ‐ビニルピロリドンであり、そして上記共重合体はポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）である。好ましくは、上記多孔質樹脂はスルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）である。
【００１７】
本発明の他の態様は少なくとも１つのイオン交換官能基、少なくとも１つの親水性成分、及び少なくとも１つの疎水性成分を含む固相抽出又はクロマトグラフィー用の多孔質樹脂である。
【００１８】
本発明の他の態様は溶質を単離又は除去するために溶液を処理する方法である。溶質を有する溶液はこの溶質が多孔質樹脂に収着するような条件下で多孔質樹脂に接触する。この多孔質樹脂は少なくとも１つのイオン交換官能基、少なくとも１つの親水性極性成分、及び少なくとも１つの疎水性成分を含む。特定の態様では、溶質は多孔質樹脂から除去される。特定の態様では、イオン交換官能基はＳＯ3Ｈ、ＣＨ2ＣＯ2Ｈ、ＣＨ2ＣＨ（ＣＯ2Ｈ）2、ＣＯ2Ｈ、ＰＯ3Ｈ2、ＰＯ2Ｈ2、ＣＨ2ＰＯ3Ｈ2、ＣＨ2Ｃｌ、ＣＨ2ＮＨ2、ＣＨ2Ｎ［（ＣＨ2）yＣＨ3］2（但しｙは０〜１８の整数である）、ＣＨ2Ｎ+［（ＣＨ2）y=ＣＨ3］3Ｄ-（但しｙ＝は０〜１８の整数そしてＤ-はアニオンである）、ＳＯ2ＮＨＲ（但しＲはポリエチレンイミンである）、又はＣＨ2ＮＨＲ（但しＲはポリエチレンイミンである）である。特定の態様では、親水性単量体は複素環式基、例えば、飽和、不飽和又は芳香族の複素環式基を含む。窒素‐含有複素環式基の例はピリジル基、例えば、２‐ビニルピリジン、３‐ビニルピリジン、又は４‐ビニルピリジンを含み、又はピロリドニル基、例えば、Ｎ‐ビニルピロリドンを含む。特定の態様では、疎水性単量体は芳香族炭素環式基、例えば、フェニル基又はフェニレン基、又は直鎖Ｃ2‐Ｃ18‐アルキル基又は枝分れＣ2‐Ｃ18‐アルキル基を含む。疎水性単量体は、例えば、スチレン又はジビニルベンゼンである。好ましい共重合体はポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）である。好ましい多孔質樹脂は化学式Ｉの化合物及びその塩である。好ましくは、多孔質樹脂はスルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）である。
【００１９】
本発明の別の特徴は溶液中の溶質の量を分析により決定する方法である。溶質を有する溶液は溶質が多孔質樹脂に収着するような条件下で多孔質樹脂と接触する。この多孔質樹脂は少なくとも１つのイオン交換官能基、少なくとも１つの親水性極性成分、及び少なくとも１つの疎水性成分を含む。収着した溶質を有する上記多孔質樹脂は上記多孔質樹脂から上記溶質を放出するような条件下で溶媒を用いて洗浄される。洗浄の後に、溶媒中に存在する上記放出した溶質の量は分析により決定される。特定の態様では、多孔質樹脂は化学式Ｉの化合物及びその塩である。好ましくは、多孔質樹脂はスルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）である。
【００２０】
本発明の別の特徴は開口容器内に詰められた多孔質樹脂を含む固相抽出カートリッジである。この多孔質樹脂は少なくとも１つのイオン交換官能基、少なくとも１つの親水性極性成分及び少なくとも１つの疎水性成分を含む。特定の態様では、多孔質樹脂は化学式Ｉの化合物及びその塩である。好ましくは、多孔質樹脂はスルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）である。
【００２１】
本発明の上記及び他の特徴、目的及び利点は図面と共に以下の明細書の記載により更によく理解できるであろう。
詳細な記述
本発明は
化学式：
【００２２】
【化１１】
の化合物及びその塩を提供し、
但し、Ａ、Ｂ及びＣの順番はランダム、ブロック、又はランダム及びブロックの組合せであり；
但し、
【００２４】
【化１２】
但し、Ａは
【００２６】
【化１３】
から成る群から選ばれ、
但し、Ｂは
【００２８】
【化１４】
から成る群から選ばれ、
但し、ＣはＡ又は修正されたＡであり、ここで、修正されたＡは
【００３０】
【化１５】
から成る群から選ばれ、そして
ここで、ＸはＳＯ3Ｈ、ＣＨ2ＣＯ2Ｈ、ＣＨ2ＣＨ（ＣＯ2Ｈ）2、ＣＯ2Ｈ、ＰＯ3Ｈ2、ＰＯ2Ｈ2、ＣＨ2ＰＯ3Ｈ2、ＣＨ2Ｃｌ、ＣＨ2ＮＨ2、ＣＨ2Ｎ［（ＣＨ2）yＣＨ3］2（但しｙは０〜１８の整数である）、ＣＨ2Ｎ+［（ＣＨ2）y=ＣＨ3］3Ｄ-（但しｙ＝は０〜１８の整数そしてＤ-はアニオンである）、ＳＯ2ＮＨＲ（但しＲはポリエチレンイミンである）、及びＣＨ2ＮＨＲ（但しＲはポリエチレンイミンである）から成る群から選ばれる。
【００３２】
好ましい化合物はＸがＳＯ3Ｈ、ＣＨ2ＰＯ3Ｈ2、ＣＨ2ＣＯ2Ｈ、又はこれらの組合せであるものである。最も好ましい化合物はＸがＳＯ3Ｈであるものである。
【００３３】
好ましくは、Ｘは化合物のグラム当り約０．０１〜約５．０ミリ当量の濃度で存在し、より好ましくは約０．６〜約３．２ミリ当量の濃度で存在し、更により好ましくは約０．８〜約２．１ミリ当量の濃度で存在し、そして最も好ましくは約１．０ミリ当量の濃度で存在する。
【００３４】
ブロックの順番はそれぞれの構成単位が一定のパターン又は一連の繰り返しで結合する順番を意味する。ランダムの順番はそれぞれの構成単位が無作為に結合する順番を意味する。
【００３５】
本発明の化合物は少なくとも１つの疎水性単量体、例えば、ジビニルベンゼン、スチレン、又はエチルビニルベンゼン、及び少なくとも１つの親水性単量体、例えば、Ｎ‐ビニルピロリドン、Ｎ‐ビニルピリジン、メタクリレート、メチルメタクリレート、酢酸ビニル、アクリルアミド又はメタクリルアミドを官能化する、即ち、化学的に変えることにより調製できる。好ましくは、疎水性単量体はジビニルベンゼンである。好ましくは、親水性単量体はＮ‐ビニルピロリドンである。上記共重合体は当業者に公知の標準的な合成法により、例えば、実施例１に記述するように調製できる。
【００３６】
このような共重合体、例えば、ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）はイオン交換官能基、Ｘ基の添加によって官能化が可能であり、これらの基は陽イオン、例えば、ＳＯ3Ｈ、ＣＨ2ＣＯ2Ｈ、ＣＨ2ＣＨ（ＣＯ2Ｈ）2、ＣＯ2Ｈ、ＰＯ3Ｈ2、ＰＯ2Ｈ2、又はＣＨ2ＰＯ3Ｈ2、又は陰イオン、例えば、ＣＨ2ＮＨ2、ＣＨ2Ｎ［（ＣＨ2）yＣＨ3］2、ＣＨ2Ｎ+［（ＣＨ2）y=ＣＨ3］3Ｄ-、ＳＯ2ＮＨＲ又はＣＨ2ＮＨＲ又は中間体、例えば、ＣＨ2Ｃｌである。これらの添加は、例えば、Lieto等のChemtechの４６〜５３頁（１９８３）；Mitchell等のTetrahedron Lettersの３７９５〜３７９８頁（１９７６）；及びクロマトグラフ科学双書，４７巻、５８５〜７２０頁（１９９０）におけるK. Ungerの“クロマトグラフ技術における充填物及び固定相”に記載されているようにして達成可能である。例えば、ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）のスルホン化を記述する実施例２を参照。
【００３７】
本発明の新規な化合物は、例えば、固相抽出及びクロマトグラフィー用の多孔質樹脂として使用できる。固相抽出は、例えば、収着、イオン交換、キレート化、サイズ排除（分子濾過）、親和力、又はイオン対の機構により、ガス及び液体のような流体相から分子化学種の部類を単離するために固相を採用する方法を意味する。
【００３８】
また本発明は少なくとも１つの疎水性単量体及び少なくとも１つの親水性単量体を共重合して共重合体を形成し、この共重合体をスルホン化反応させて少なくとも１つのイオン交換官能基、少なくとも１つの疎水性成分、及び少なくとも１つの親水性成分を含むスルホン化共重合体を形成することにより得られる多孔質樹脂を含む。
【００３９】
多孔質樹脂は溶液が拡散できる通路を通って浸透する架橋重合体粒子の部類のメンバーを意味する。気孔は密に詰め込まれた重合体鎖の間の領域を意味する。単量体は重合前の１又はそれ以上の重合可能な官能基を含む分子、又は重合体の繰返し単位を意味する。共重合体は２又はそれ以上の異なる単量体を含む重合体を意味する。イオン交換官能基は対イオンが部分的に遊離し、そして同じ符号の別のイオンと容易に交換できる基を意味する。親水性は水を引付け、吸着し、又は吸収するための親和力を持つことを意味する。疎水性は水をはじき、又は水を吸着又は吸収する親和力を持たないことを意味する。
【００４０】
好ましい態様では、疎水性単量体はジビニルベンゼンである。好ましい態様では、親水性単量体はＮ‐ビニルピロリドンである。好ましい態様では、共重合体はポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）である。好ましい態様において、多孔質樹脂はスルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）である。好ましくは、スルホン酸塩基は多孔質樹脂のグラム当り、約０．０１〜約５．０、より好ましくは約０．６〜約３．２、更により好ましくは約０．８〜約２．１、そして最も好ましくは約１．０ミリ当量の濃度で存在する。
【００４１】
また本発明は少なくとも１つのイオン交換官能基、少なくとも１つの親水性成分、及び少なくとも１つの疎水性成分を含有する固相抽出又はクロマトグラフィー用の多孔質樹脂を含む。
【００４２】
イオン交換官能基は多孔質樹脂を塩基性で陽イオンの溶質と相互反応させることができる。親水性極性成分は溶質に対する極性相互作用及び水素結合能力を多孔質樹脂に持たせることができる。疎水性成分は疎水性相互作用を通じて無極性溶質に対する親和力を多孔質樹脂に持たせることができる。本発明の多孔質樹脂は溶質に対して種々の相互作用力の組み合わせを有するため、これらは、例えば、固相抽出、イオン交換、液体クロマトグラフィーの用途において極めて有用な樹脂である。例えば、これらの新規な多孔質樹脂は流体から溶質を回収し、固定し、及び／又は除去できる。
【００４３】
また本発明は溶液を処理して溶質を単離又は除去する方法を含む。溶質を有する溶液は多孔質樹脂に溶質が収着するような条件下で多孔質樹脂に接触する。この多孔質樹脂は少なくとも１つのイオン交換官能基、少なくとも１つの親水性成分、及び少なくとも１つの疎水性成分を含む。ある態様では、溶質は多孔質樹脂から除去される。
【００４４】
収着は吸収又は吸着により取り上げて保持できることを意味する。
ある態様において、イオン交換官能基はＳＯ3Ｈ、ＣＨ2ＣＯ2Ｈ、ＣＨ2ＣＨ（ＣＯ2Ｈ）2、ＣＯ2Ｈ、ＰＯ3Ｈ2、ＰＯ2Ｈ2、ＣＨ2ＰＯ3Ｈ2、ＣＨ2Ｃｌ、ＣＨ2ＮＨ2、ＣＨ2Ｎ［（ＣＨ2）yＣＨ3］2（但しｙは０〜１８の整数である）、ＣＨ2Ｎ+［（ＣＨ2）y=ＣＨ3］3Ｄ-（但しｙ＝は０〜１８の整数そしてＤ-はアニオンである）、ＳＯ2ＮＨＲ（但しＲはポリエチレンイミンである）、又はＣＨ2ＮＨＲ（但しＲはポリエチレンイミンである）である。好ましくは、イオン交換官能基はＳＯ3Ｈである。好ましくは、イオン交換官能基は多孔質樹脂のグラム当り、約０．０１〜約５．０、より好ましくは約０．６〜約３．２、更により好ましくは約０．８〜約２．１、そして最も好ましくは約１．０ミリ当量の濃度で存在する。
【００４５】
ある態様において、親水性極性成分はアミド基、エステル基、カーボネート基、カルバメート基、尿素基、ヒドロキシ基、又はピリジル基である。
ある態様において、多孔質樹脂は少なくとも１つのイオン交換官能基を有する共重合体を含み、そしてこの共重合体は少なくとも１つの親水性単量体及び少なくとも１つの疎水性単量体を含む。好ましくは、親水性単量体は複素環式基、例えば、飽和、不飽和又は芳香族の複素環式基を含む。例としては、窒素‐含有複素環式基、例えば、ピリジル基、例えば、２‐ビニルピリジン、３‐ビニルピリジン、又は４‐ビニルピリジンを含み、又はピロリドニル基、例えば、Ｎ‐ビニルピロリドンを含む。好ましくは、疎水性単量体は芳香族炭素環式基、例えば、フェニル基又はフェニレン基、又は直鎖Ｃ2‐Ｃ18‐アルキル基又は枝分れＣ2‐Ｃ18‐アルキル基を含む。疎水性単量体は、例えば、スチレン又はジビニルベンゼンである。好ましい共重合体はポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）である。
【００４６】
好ましい多孔質樹脂は上述した化学式Ｉの化合物及びその塩である。好ましくは、多孔質樹脂はスルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）である。
【００４７】
好ましい態様では、多孔質樹脂は少なくとも約１２モルパーセントのＮ‐ビニルピロリドンを含む。好ましい態様では、多孔質樹脂は約３０モルパーセントより少ないＮ‐ビニルピロリドンを含む。モルパーセントは多孔質樹脂の共重合体を構成する種々の（２又はそれ以上の）単量体の合計モルに対する対象の単量体の、パーセントで表示された、モル分率を意味する。好ましくは、多孔質樹脂は固相抽出能力を有する。
【００４８】
多孔質樹脂は、例えば、ビーズ、ペレット、又は用途に応じたその他の形状であってもよい。多孔質樹脂粒子は、例えば、球形、規則的な形状、又は不規則な形状を持つことができる。好ましくは、上記樹脂粒子は約３〜約５００μｍ、より好ましくは約２０〜約２００μｍの範囲の直径を有するビーズである。好ましくは、多孔質樹脂はグラム当り約５０〜約８５０平方メートルの範囲の比表面積と約０．５ｎｍ〜約１００ｎｍの範囲の直径を有する。ある態様では、多孔質樹脂はマトリックス中に入れられる。
【００４９】
ある態様において、２種類以上の官能化多孔質樹脂が本発明のカラム、カートリッジ及び類似物中で使用できる。
溶質は、例えば、疎水性、親水性、又はイオンの相互作用又はこれらの相互作用の２又は３種の組合せを有する分子であってもよい。好ましくは、溶質は多孔質樹脂に吸着されるのに適した極性を有する有機化合物である。このような溶質は、例えば、薬剤、農薬、除草剤、毒物及び環境汚染物質、例えば、地下燃料又は水銀、鉛又はカドミウムのような重金属を含む金属‐有機化合物のような他の工業物質の燃焼により生じる物質を含む。また溶質は上記物質の代謝物質又は分解生成物であってもよい。また溶質は、例えば、蛋白質、ペプチド、ホルモン、ポリヌクレオチド、ビタミン、補因子、代謝物質、脂質のような生体分子、及び炭水化物を含む。
【００５０】
溶液は、例えば、水、水溶液、水又は水溶液の混合物、及び水‐混和性極性有機溶媒、例えば、メタノール、エタノール、Ｎ，Ｎ‐ジメチルホルムアミド、ジメチルスルホキシド又はアセトニトリルを含むことができる。好ましい態様では、溶液は酸性、塩基性又は中性の水溶液、即ち、約１％〜約９９％水容量の溶液である。溶質を含む溶液は任意に更に１又はそれ以上の別の溶質を含むことができる。ある態様において、溶液は種々の溶質の錯体を含む水溶液である。この形式の溶液は、例えば、血液、血漿、尿、髄液、滑液、及び肝臓組織、筋肉組織、脳組織又は心臓組織のような組織の抽出物を含むその他の生物的液体を含む。これらの抽出物は、例えば、水性又は有機の抽出物であってもよく、これらは乾燥後に水又は水／有機混合物中に戻される。また溶液は、例えば、地下水、地上水、飲料水、又は土壌サンプルのような環境サンプルの水性又は有機抽出物を含む。溶液の他の例は果物や野菜のジュース又はミルクのような食品、又は果物、野菜、穀物又は肉のような食物の水性又は水性／有機抽出物を含む。その他の溶液は、例えば、植物及びスープからの天然抽出物を含む。
【００５１】
溶液はバッチ又はクロマトグラフ法のように、溶質を多孔質樹脂に収着させる方法で多孔質樹脂に接触できる。例えば、溶液は多孔質重合体カラム、ディスク又はプラグに通されてもよいし、又は溶液はバッチ‐撹拌反応器内で多孔質樹脂と撹拌されてもよい。また溶液はマイクロタイター(microtiter)板から成る多孔質樹脂‐含有ウエル(well)に加えられてもよい。多孔質樹脂は、例えば、ビーズ又はペレットの形状を成すこともできる。溶液は溶質が多孔質樹脂上に実質的に収着するのに十分な時間で多孔質樹脂に接触する。この時間は溶質が多孔質樹脂表面と溶液との間で平衡になるのに必要な時間である。多孔質樹脂上への溶質の収着又は分割は部分的又は完全である。
【００５２】
ある態様では、多孔質樹脂は開口容器内の粒子として充填されて固相抽出カートリッジを形成する。
また本発明は溶液中の溶質の量を分析により決定する方法を含む。溶質を有する溶液は多孔質樹脂への溶質の収着を許容するような条件下で多孔質樹脂と接触する。上記多孔質樹脂は少なくとも１つのイオン交換官能基、少なくとも１つの親水性極性成分、及び少なくとも１つの疎水性成分を含む。上記収着した溶質を有する多孔質樹脂は多孔質樹脂から溶質を放出するような条件下で溶媒により洗浄される。上記洗浄の後に、溶媒中に存在する上記放出した溶質の量が分析により決定される。
【００５３】
ある態様において、多孔質樹脂は化学式Ｉの化合物及びその塩である。好ましくは、多孔質樹脂はスルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）である。
【００５４】
多孔質樹脂に接触する溶液は目的の溶質を希釈された形で、例えば、正確な定量には低すぎる濃度で含むことができる。溶質を多孔質樹脂上に収着し、次いで、例えば、実質的に小容量の極性の小さい溶媒を用いて脱着することにより、目的の溶質を含有し、最初の溶液よりも溶質の濃度が実質的に高い溶液を調製できる。この方法は溶媒交換が可能、即ち、溶媒は第１溶媒から除去され、そして第２溶媒に再溶解できる。
【００５５】
溶質を多孔質樹脂から脱着するのに適する溶媒は、極性水‐混和性有機溶媒、例えば、メタノール、エタノール、イソプロパノールのようなアルコール、又はアセトニトリル、アセトン、テトラヒドロフラン、又は水及びこれらの溶媒の混合物である。また脱着溶媒は、例えば、ジクロロメタン、ジエチルエーテル、クロロホルム、又は酢酸エチルのような非極性又は適度に極性の水‐非混和性溶媒である。これらの溶媒の混合物も好適である。好ましい溶媒又は溶媒混合物はそれぞれ別個のケースに応じて決定されるべきである。好ましい溶媒はクロマトグラフ法において、日常的に行われているため、不当な実験を行うことなく、当業者が決定できる（例えば、McDonald及びBouvier, eds., の固相抽出の適用ガイド及び参考文献の“サンプル調製法の進歩のための資源”６巻、Waters, Milford, MA（１９９５）；及びSnyder及びKirkland、最新の液体クロマトグラフィー入門、ニューヨーク：J. Wiley及びSons（１９７４）を参照）。
【００５６】
溶媒中に存在する脱着された溶媒の量は当業者に知られている種々の技術、例えば、高性能液体クロマトグラフィー、ガスクロマトグラフィー、ガスクロマトグラフィー／質量分析、又はイムノアッセイにより分析的に決定できる。
【００５７】
また本発明は開口容器内に詰められた多孔質樹脂を含む固相抽出カートリッジを含む。この多孔質樹脂は少なくとも１つのイオン交換官能基、少なくとも１つの親水性極性成分及び少なくとも１つの疎水性成分を含む。特定の態様では、多孔質樹脂は上述の化学式Ｉの化合物及びその塩である。好ましくは、多孔質樹脂はスルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）である。
【００５８】
容器は、例えば、両端が開放した円筒形の容器又はカラムであって、溶液は一端を通って容器内に入り、容器内の多孔質樹脂と接触し、そして他端を通って容器から出る。多孔質樹脂は約３μｍ〜約５００μｍ、好ましくは約２０μｍ〜約２００μｍの直径を有するビーズのような小粒子として容器内に充填できる。ある態様では、多孔質樹脂粒子は多孔質膜の網にかけられた状態で容器内に充填できる。
【００５９】
容器は固相抽出プロセスの時間枠内において、工程で使用される溶液と溶媒に適合できる材料から形成できる。このような材料はガラス又は高密度ポリエチレン及びポリプロピレンのような種々のプラスチックを含む。ある態様では、容器はその大部分が円筒形であり、そして一端に狭い先端を有する。このような容器の一例はシリンジバレルである。容器内の多孔質樹脂の量は容器の容積により制限され、そして約０．００１グラム〜約５０キログラム、好ましくは約０．０２５グラム〜約１グラムの範囲内にある。所望の抽出に適する多孔質樹脂の量は収着される溶質の量、多孔質樹脂の利用される表面積、及び溶質と多孔質樹脂との間の相互作用の強度に依存する。この量は当業者により容易に決定できる。カートリッジは単一使用のカートリッジであって、単一サンプルの処理に使用された後に、廃棄されてもよく、又は複数サンプルの処理に使用できる。
【００６０】
以下の非限定的実施例は更に本発明を説明する。
実施例
実施例１： ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）共重合
の調製
この実施例はポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）共重合の調製を説明する。
【００６１】
５．０グラムのヒドロキシプロピルメチルセルロース（Methocel E15、ダウケミカル会社、Midland、ミシガン州）を１０００ミリリットルの水に溶かした溶液を３０００ミリリットルのフラスコに加えた。これに１７５グラムのジビニルベンゼン（DVB HP-80、ダウケミカル）、１０２グラムのＮ‐ビニル‐２‐ピロリドン（International Specialty Products、Wayne、ニュージャージー州）、及び１．８５グラムのアゾビスイソブチロニトリル（Vazo 64、デュポンケミカル会社、Wilmington、デラウエア州）を２４２グラムのトルエンに溶かした溶液を加えた。
【００６２】
上記８０％純度のジビニルベンゼンはスチレン又はエチルビニルベンゼン、又は低純度のジビニルベンゼンのような他の疎水性単量体と置換されてもよいが、しかし８０％純度のジビニルベンゼンが好ましい。上記Ｎ‐ビニルピロリドンはＮ‐ビニル‐ピリジン、メタクリレート、メチルメタクリレート、酢酸ビニル、アクリルアミド、又はメタクリルアミドのような他の親水性単量体と置換されてもよいが、しかしＮ‐ビニルピロリドンが好ましい。
【００６３】
得られた２相の混合物を室温で３０分間撹拌して、所望のミクロン寸法の油滴を形成した。次いで得られた懸濁液を適度に撹拌しながら、７０℃まで加熱し、そしてこの温度で２０時間維持した。この懸濁液を室温まで冷却し、濾過し、そしてメタノールで洗浄した。この濾過ケークを真空中で８０℃で１６時間乾燥した。生成物重合体の組成を元素分析により決定した。元素分析：Ｎ：２．２４％； モルパーセントＮ‐ビニルピロリドン：２０％。
【００６４】
またこの方法によりジビニルベンゼンとＮ‐ビニルピロリドンの出発比率を変化させることにより、約１３、１４、１６、及び２２モルパーセントのＮ‐ビニルピロリドンを含む一連のポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）共重合体を調製した。
実施例２： ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）共重合
のスルホン化
この実施例はスルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）多孔質樹脂の調製を説明する。実施例１から得た共重合体、好ましくはポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）は硫酸（９５‐９８％、A. C. S. 試薬、Aldrich、２５，８１０‐５、Milwaukee、ウイスコンシン州）で誘導できる。最も好ましくは、OASIS（登録商標）HLB（Waters株式会社、Milford、マサチューセッツ州から入手)が使用される。
【００６５】
プロセス設計及び品質管理のための指針として役立ち得る。
式１： 共重合体（ｍｅｑ ＨＳＯ3／ｇスルホン化共重合体）のイオン
交換能力＝０．５３＋０．０１８×［温度］＋０．０００２９
×［時間］
ここで、［温度］＝反応温度（℃）
［時間］＝反応時間（分）
【００６６】
【表１】
実施例３： スルホン化樹脂のクロマトグラフ保持挙動に関するスルホン化の
効果
この実施例はスルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）樹脂のスルホン化の程度が樹脂の疎水性及びイオン交換性の挙動並びに樹脂の保持特性にどのように影響を与えるかを示す。
【００６８】
実施例２から得られた樹脂のＪＪＬ０３‐９０，１００，１１４，１１９，１２３，１２４，及び１４３をそれぞれ４．６×３０ｍｍの高性能液体クロマトグラフィー（ＨＰＬＣ）カラム中にスラリー状で充填した。疎水性の保持及びイオン交換の挙動に関するスルホン化の効果を種々の中性及び塩基性の検体の保持力を検査することにより決定した。選ばれたモデル化合物はアセトアミノフェン、ｐ‐トルアミド、カフェイン、プロカインアミド、ラニチジン（ｒａｎｉｔｉｄｉｎｅ）、アンフェタミン、メスアンフェタミン（ｍｅｔｈａｎｐｈｅｔａｍｉｎｅ）及びｍ‐トルイジンであった。これらのモデル化合物を図１に示す。移動相を４０：６０メタノール‐２０ｍＭ（ＮＨ4）Ｈ2ＰＯ4から構成し、ＮＨ4Ｃｌをイオン強度調節剤として用いてｐＨを３．０とした。流量は１．０ｍＬ／分、温度は３０℃であった。注入容量は５マイクロリットルであった。各化合物は別々に注入された。検出を２５４ｎｍの紫外線により実施した。
【００６９】
疎水性又はイオン性の機構による相互作用が存在するか否かを決定するために、保持挙動をイオン強度の関数として決定した。図２Ａ及び２Ｂは非スルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）（Ｏａｓｉｓ（登録商標）ＨＬＢ、バッチ６Ｂ）、及び比較的多くスルホン化されたポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）（バッチＪＪＬ０３‐１００）（２．５２ｍｅｑ／ｇ）について、保持に基づくイオン強度の効果を示す。非スルホン化樹脂から判るように、イオン強度の増大につれて、全ての成分について保持力の増大は極めて僅かであった。この結果は疎水性の相互作用の機構と一致する。また非スルホン化樹脂について、保持係数が−＜１の場合、使用される条件下において塩基性化合物の疎水性保持力はほんの僅かであった。スルホン化樹脂の場合、中性化合物の保持力はほとんど変化しないことが判明した。しかしながら、塩基性化合物の保持力はイオン強度によって劇的に影響された。保持力はイオン強度の増大と共に著しく増大し、これはイオン交換機構を示唆する。
【００７０】
図３は保持力に基づく樹脂のスルホン化の効果を示す。１ＭのＮＨ4Ｃｌが保持時間を最小にするために使用された。このグラフは中性化合物の保持力がスルホン化の増大につれて減少したことを示す。塩基性化合物については、保持力はスルホン化が１ｍｅｑ／ｇにまで増大するにつれて増大した。しかしながら、より高いスルホン化のレベルにおいては、保持力は再び減少した。
実施例４： スルホン化樹脂の固相抽出の実施に基づくスルホン化の効果
この実施例はスルホン化樹脂の固相抽出（ＳＰＥ）の実施に基づくこの樹脂のスルホン化の効果を説明する。
【００７１】
ＳＰＥの実施を評価するために、ＨＰＬＣ法を採用して、いくつかのモデル化合物の回収を検証した。SymmetryShield（登録商標）RP8カラム、３．５μｍ、４．６×７５ｍｍ（Waters株式会社、Milford、マサチューセッツ州)をSentry（登録商標）カラム（Waters株式会社、Milford、マサチューセッツ州)と共にインラインで使用した。流量は２．０ミリリットル／分、温度は３６℃であった。移動相を９５：５ ２０ｍＭ Ｋ2ＨＰＯ4、ｐＨ７．０‐メタノールから構成した。検出を２５４ｎｍの紫外線により実施した。注入容量は１０μＬであった。最適な分離を示すクロマトグラムを図４に示す。
【００７２】
ＳＰＥの評価のために、次の樹脂、即ち、Oasis（登録商標）HLBバッチ#6B、JJL03-143、JJL03-124及びJJL03-100を使用した。９６‐ウエルプレート形態で吸収剤をそれぞれ３０ミリグラム使用してＳＰＥを実施した。工程は以下の通りである。上記カートリッジ／ウェルを１ミリリットルのメタノール（−１ｍＬ／分）で状態調整し、次いで１ミリリットルの水で平衡にした。スパイクされた(spiked)リン酸塩で緩衝された生理食塩水又はスパイクされた豚の血漿から成る１ミリリットルのサンプルを導入した。サンプルはアセトアミノフェン、トルアミド、カフェイン及びプロカインアミドを１０μｇ／ｍＬまでスパイクされ、そしてアンフェタミン、メスアンフェタミン及びトルイジンを２０μｇ／ｍＬまでスパイクされた。導入されたサンプルを０．１ＭのＨＣｌを１ミリリットル含む水で洗浄し、次いで１ミリリットルのメタノールで洗浄し、そして２％のＮＨ4ＯＨを含有する１ミリリットルのメタノールの１／２で溶離した。平衡の後に、全ての画分を集めた。１０μｇ／ｍＬのラニチジン(ranitidine)の５０μＬをそれぞれのサンプルに加えた。このサンプルを加熱ブロック内のＮ2流の下で蒸発させて乾燥した。次いでサンプルを１ミリリットルの２０ｍＭリン酸塩緩衝液（ｐＨ７．０）で復元した。
【００７３】
最初のＳＰＥ性能実験をリン酸塩‐緩衝生理食塩水中で実施した。完全な物質収支がスルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）、バッチ#JJL03-143を使用してＳＰＥ画分に対して実行された。表２は回収と物質収支の結果を示す。
【００７４】
【表２】
アンフェタミン、メスアンフェタミン及びトルイジンは全てのケースにおいて、十分に回収できなかった。これはこれらの化合物が半‐揮発性であるため、蒸発を通じて失われることに起因する。サンプルが乾燥していない実験例では、完全な回収が得られた。生理食塩水を回収して調べた結果、漏出はいかなる場合でも添加又はＨＣｌ洗浄工程において生じなかった。全ての化合物がOasis（登録商標）HLBに対するメタノール洗浄において溶離したが、中性化合物のみが全てのスルホン化樹脂に対して溶離した。塩基性化合物はメタノール／ＮＨ4ＯＨ溶液によって完全に溶離した。スルホン化樹脂に関しては、ほとんどのカフェインが最初のメタノール洗浄で溶離した。また各画分の回収はスルホン化の程度に依存し、スルホン化が最小の樹脂は最初のメタノール洗浄で回収が最大になることが判明した。この異常な結果はカフェインが１３．９のｐＫbを有する弱塩基であることに起因する。別の観察によれば、アセトアミノフェンはスルホン化樹脂に関してメタノール／塩基の溶離において僅かな量の漏出（−１％）を示した。
【００７６】
類似の結果が血漿を用いた場合に得られた。表３は３種類の異なる吸収剤のOasis（登録商標）HLBバッチ6B、JJL03-100及びJJL03-124について得られた回収の結果を示す。
【００７７】
【表３】
中性物質はメタノール洗浄において溶離し、塩基はメタノール／水酸化アンモニウム工程において溶離した。スルホン化樹脂からのスパイクされない血漿抽出物のＨＰＬＣ分析を図５Ａ及び５Ｂに示し、ここでラニチジンが内標準である。
【００８０】
抽出物中の蛋白質をクマシーブルー(Coomassie blue)によって計量した。血漿の２つの異なるロットを試験した。結果を表４に示す。
【００８１】
【表４】
塩基化されたメタノール中の蛋白質はOasis（登録商標）HLB、JJL03-100及びJJL03-124について類似点があることが判明した。比較として、（メタノール溶離工程からの）Oasis（登録商標）HLBカートリッジについて、これらの蛋白質量は推奨されるＳＰＥプロトコール（“Water Oasis（登録商標）HLB抽出カートリッジ及びプレート”１９９７ Waters 株式会社、６／９７ＷＢ０２５‐ＵＳ）を用いて典型的に観察されるものより約５倍も少なかった。
【００８３】
高いスルホン化ローディング(loadings)において、樹脂を通過する血漿ロード(load)は懸濁した。関連の観察の結果、流量は高いスルホン化ローディングにおいて減少することが判明した。これらの観察結果は樹脂の酸性度に起因する。大部分のスルホン化樹脂は最も高い酸性度を有する。従って、血漿を樹脂に通すことは酸性の沈殿物を生成させること相当し、これはサンプルをより懸濁させ、そしてフリット及び樹脂含有充填ベッドを塞ぐことになる。
実施例５： ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）多孔質
樹脂のクロロメチル化
ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）、OASIS（登録商標）HLB、（Waters株式会社、Milford、マサチューセッツ州)を塩酸（１２モル、３６．５〜３８％、A.C.S.試薬、J.T.Baker、９５３５‐０３、Phillipsburgh、ニュージャージー州）及びパラホルムアルデヒド（９５％、Aldrich Chemical、１５，８１２‐７、Milwaukee、ウイスコンシン州）で誘導した。３リットルの三つ口の丸底フラスコに温度計、撹拌機、凝縮器、及び反応器温度制御装置を取り付けた。塩酸を上記フラスコ中に導入した（塩酸の量に関しては表５を参照）。次いで撹拌及び温度制御を行った。撹拌機はフラスコ頂部の中心開口内に適当なテフロンベアリングを介してすりガラスシャフトにより固定された。テフロンパドルは単一羽根であった。撹拌速度を適切な混合を得るために調節した。ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）、OASIS（登録商標）HLBを添加した（OASIS（登録商標）HLBの量に関しては表５を参照）。次いでパラホルムアルデヒドを添加した（パラホルムアルデヒドの量に関しては表５を参照）。反応混合物を特定時間、一定の温度で撹拌した（反応時間及び温度に関しては表５を参照）。反応混合物を冷却し、そして酸溶液を濾過した。クロロメチル化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）共重合体を収集し、そしてスラリーのｐＨが５．０以上になるまで水で洗浄した。次いでクロロメチル化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）共重合体の濾過ケークをメタノール（HPLC等級、J.T. Baker、９５３５‐０３、Phillipsburgh、ニュージャージー州）で２回洗浄し、そして真空中において８０℃で１５時間乾燥した。クロロメチル化の程度を塩素元素分析（Atlantic Microlab株式会社、Norcross、ジョージア州）により決定した。上記共重合体上のクロロメチル基（ＣＨ2Ｃｌ）の量を表５に示す。
【００８４】
反応時間、反応温度、及び塩酸モル濃度は全てポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）共重合体へのクロロメチル基の付与量に影響を与えることが判明した。これら３種類の変数の種々の組合せ及びその結果のクロロメチル付与量を表５に示す。
【００８５】
【表５】
実施例６： クロロメチル化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロ
リドン）多孔質樹脂のアミノ化
実施例５で述べたように調製されたクロロメチル化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）多孔質樹脂を次の第三アミン（全てをAldrich Chemical、Milwaukee、ウイスコンシン州から購入）、即ちトリメチルアミン（TMA、４０重量％水溶液、４３、３２６‐８）、トリエチルアミン（TEA、９９％、１３、２０６‐３）、Ｎ，Ｎ‐ジメチルエチルアミン（DMEA、９９％、2３、９３５‐６）、Ｎ，Ｎ‐ジエチルメチルアミン（DEMA、９８％、Ｄ９、８２０‐３）、Ｎ，Ｎ‐ジメチルブチルアミン（DMBA、９９％、３６、９５２‐７）、及びＮ‐メチルピロリドン（NMP、９７％、Ｍ７、９２０‐４）と反応させた。一般的なアミノ化の手順を以下に示す。反応アミンアルキル基のクロロメチル化ロード(load)及び立体サイズ（Hirsch, J.A. 立体化学における話題、第１巻、Allinger, N.L.； Eliel, E.D., Eds. Wiley: ニューヨーク、１９６７、第１章）はポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）共重合体上へのアンモニウム基のローディングに通常影響を与えることが判明した。一般的な反応の手順を以下に示す。工程１のクロロメチルのローディング、アミンの種類、及び反応温度の種々の組合せ、及び得られる第４アミンのローディングを表６に示す。
【００８７】
２５０ミリリットルの三つ口の丸底フラスコに温度計、撹拌機、凝縮器、及び反応器温度制御装置を取り付けた。トリアルキルアミンを上記フラスコ内に導入し（それぞれのアミンの量に関しては表６を参照）、そして撹拌及び温度制御を開始した。撹拌機はフラスコ頂部の中心開口内に適当なテフロンベアリングを介してすりガラスシャフトにより固定された。テフロンパドルは単一羽根であった。クロロメチル化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）を添加（樹脂の量に関しては表６を参照）し、そして充分な混合を得るために撹拌速度を調節した。反応混合物を特定時間、一定の温度で撹拌した（反応時間及び温度に関しては表６を参照）。反応混合物を冷却し、そしてアミンを濾過した。アミン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）共重合体を収集し、そしてスラリーのｐＨが５．５以下になるまで水で洗浄した。次いでアミノ化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）共重合体の濾過ケークをメタノール（HPLC等級、J.T. Baker、９５３５‐０３、Phillipsburgh、ニュージャージー州）で２回洗浄し、そして真空中において８０℃で１５時間乾燥した。アミノ化の程度を滴定により決定した。上記共重合体上のメチレントリアルキルアンモニウム基（ＣＨ2ＮＲ3 +Ｃｌ-）の量を表６に示す。
【００８８】
【表６】
結論として、上記実験によれば、スルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）は塩基性化合物のＳＰＥのために通常の方法で使用できることが実証された。またこれは中性及び塩基性化合物のクラス分別を達成する道具として使用できる。
【００９０】
当業者は普通の実験を使用するだけで上述した本発明の具体例と同等の物を数多く確認できるであろう。これらのそして全ての同等物は上述のクレイムの保護範囲内にある。
［本発明の態様］
［１］
化学式：
【化１】
但し、
【化２】
【化３】
但し、Ｂは
【化４】
【化５】
ここで、ＸはＳＯ 3 Ｈ、ＣＨ 2 ＣＯ 2 Ｈ、ＣＨ 2 ＣＨ（ＣＯ 2 Ｈ） 2 、ＣＯ 2 Ｈ、ＰＯ 3 Ｈ 2 、ＰＯ 2 Ｈ 2 、ＣＨ 2 ＰＯ 3 Ｈ 2 、ＣＨ 2 Ｃｌ、ＣＨ 2 ＮＨ 2 、ＣＨ 2 Ｎ［（ＣＨ 2 ） y ＣＨ 3 ］ 2 （但しｙは０〜１８の整数である）、ＣＨ 2 Ｎ + ［（ＣＨ 2 ） y= ＣＨ 3 ］ 3 Ｄ - （但しｙ＝は０〜１８の整数そしてＤ - はアニオンである）、ＳＯ 2 ＮＨＲ（但しＲはポリエチレンイミンである）、及びＣＨ 2 ＮＨＲ（但しＲはポリエチレンイミンである）から成る群から選ばれる上記化合物及びその塩。
［２］
Ｘは化合物のグラム当り約０．１〜約５．０ミリ当量の濃度で存在する１の化合物。
［３］
Ｘは化合物のグラム当り約０．６〜約３．２ミリ当量の濃度で存在する１の化合物。
［４］
Ｘは化合物のグラム当り約０．８〜約２．１ミリ当量の濃度で存在する１の化合物。
［５］
Ｘは化合物のグラム当り約１．０ミリ当量の濃度で存在する１の化合物。
［６］
ＸはＳＯ 3 Ｈ、ＣＨ 2 ＰＯ 3 Ｈ 2 、及びＣＨ 2 ＣＯ 2 Ｈから成る群から選ばれる１の化合物。
［７］
ＸはＳＯ 3 Ｈである６の化合物。
［８］
少なくとも１つの疎水性単量体と少なくとも１つの親水性単量体を共重合させて共重合体を生成し、そして上記共重合体をスルホン化反応させて、少なくとも１つのイオン交換官能基、少なくとも１つの親水性成分、及び少なくとも１つの疎水性成分を含むスルホン化共重合体を生成することにより得られる固相抽出又はクロマトグラフィー用の多孔質樹脂。
［９］
上記疎水性単量体はジビニルベンゼンである８の多孔質樹脂。
［１０］
上記親水性単量体はＮ‐ビニルピロリドンである８の多孔質樹脂。
［１１］
上記共重合体はポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）である８の多孔質樹脂。
［１２］
上記多孔質樹脂はスルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）である８の多孔質樹脂。
［１３］
上記スルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）は多孔質樹脂のグラム当り約０．１〜約５．０ミリ当量の濃度で存在するスルホン酸塩の基を有する１２の多孔質樹脂。
［１４］
少なくとも１つのイオン交換官能基、少なくとも１つの親水性成分、及び少なくとも１つの疎水性成分を含む固相抽出又はクロマトグラフィー用の多孔質樹脂。
［１５］
溶質を単離又は除去するために溶液を処理する方法であって、 溶質を有する溶液を多孔質樹脂と上記溶質が上記多孔質樹脂に収着するような条件下で接触させることを含み；
上記多孔質樹脂は少なくとも１つのイオン交換官能基、少なくとも１つの親水性極性成分、及び少なくとも１つの疎水性成分を含む： 上記方法。
［１６］
上記イオン交換官能基はＳＯ 3 Ｈ、ＣＨ 2 ＣＯ 2 Ｈ、ＣＨ 2 ＣＨ（ＣＯ 2 Ｈ） 2 、ＣＯ 2 Ｈ、ＰＯ 3 Ｈ 2 、ＰＯ 2 Ｈ 2 、ＣＨ 2 ＰＯ 3 Ｈ 2 、ＣＨ 2 Ｃｌ、ＣＨ 2 ＮＨ 2 、ＣＨ 2 Ｎ［（ＣＨ 2 ） y ＣＨ 3 ］ 2 （但しｙは０〜１８の整数である）、ＣＨ 2 Ｎ + ［（ＣＨ 2 ） y= ＣＨ 3 ］ 3 Ｄ - （但しｙ＝は０〜１８の整数そしてＤ - はアニオンである）、ＳＯ 2 ＮＨＲ（但しＲはポリエチレンイミンである）、及びＣＨ 2 ＮＨＲ（但しＲはポリエチレンイミンである）から成る群から選ばれる１４の方法。
［１７］
上記イオン交換官能基はＳＯ 3 Ｈ、ＣＨ 2 ＰＯ 3 Ｈ 2 、及びＣＨ 2 ＣＯ 2 Ｈから成る群から選ばれる１６の方法。
［１８］
上記イオン交換官能基はＳＯ 3 Ｈである１７の方法。
［１９］
上記イオン交換官能基は多孔質樹脂のグラム当り約０．１〜約５．０ミリ当量の濃度で存在する１５の方法。
［２０］
上記親水性極性成分はアミド基、エステル基、カーボネート基、カルバメート基、尿素基、ヒドロキシ基、及びピリジル基から成る群から選ばれる１５の方法。
［２１］
上記多孔質樹脂は少なくとも１つのイオン交換官能基を有する共重合体を含み、上記共重合体は少なくとも１つの親水性単量体及び少なくとも１つの疎水性単量体を含む１５の方法。
［２２］
上記親水性単量体は複素環式基を含む２１の方法。
［２３］
上記複素環式基はピリジル基又はピロリドニル基である２２の方法。
［２４］
上記ピリジル基は２‐ビニルピリジン、３‐ビニルピリジン、及び４‐ビニルピリジンから成る群から選ばれる２３の方法。
［２５］
上記ピロリドニル基はＮ‐ビニルピロリドンである２３の方法。
［２６］
上記疎水性単量体はフェニル基、フェニレン基、直鎖Ｃ 2 ‐Ｃ 18 ‐アルキル基及び枝分れＣ 2 ‐Ｃ 18 ‐アルキル基から成る群から選ばれる基を含む２１の方法。
［２７］
上記疎水性単量体はスチレン又はジビニルベンゼンである２６の方法。
［２８］
上記疎水性単量体はジビニルベンゼンである２６の方法。
［２９］
上記共重合体はポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）である２１の方法。
［３０］
上記多孔質樹脂は化学式Ｉの化合物及びその塩である１５の方法。
［３１］
上記多孔質樹脂はスルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）である１５の方法。
［３２］
上記スルホン酸塩基は多孔質樹脂のグラム当り約０．１〜約５．０ミリ当量の濃度で存在する３１の方法。
［３３］
上記多孔質樹脂は少なくとも約１２モルパーセントのＮ‐ビニルピロリドンを含む３１の方法。
［３４］
上記多孔質樹脂は約３０モルパーセントより少ないＮ‐ビニルピロリドンを含む３１の方法。
［３５］
上記多孔質樹脂はビーズの形状である１５の方法。
［３６］
上記ビーズは約３〜約５００マイクロメーターの平均寸法を有する３５の方法。
［３７］
上記多孔質樹脂はマトリックス中に入れられる１５の方法。
［３８］
上記多孔質樹脂は固相抽出能力を有する１５の方法。
［３９］
上記溶質は薬剤、農薬、除草剤、生体分子、毒物、汚染物質、代謝物、及びこれらの分解生成物から成る群から選ばれる１５の方法。
［４０］
上記溶液は水、水溶液、水又は水溶液の混合物、及び水‐混和性極性有機溶媒から成る群から選ばれる１５の方法。
［４１］
上記溶液は血液、血漿、尿、髄液、滑液、組織抽出物、地下水、地上水、飲料水、土壌抽出物、食糧物質、食糧物質の抽出物、植物及びブイヨンからの天然抽出物から成る群から選ばれる１５の方法。
［４２］
上記多孔質樹脂は開口容器内にある１５の方法。
［４３］
上記多孔質樹脂から上記溶質を除去する工程を更に含む１５の方法。
［４４］
溶液中の溶質の量を分析により決定する方法であって、 溶質を有する溶液を多孔質樹脂と上記溶質が上記多孔質樹脂に収着するような条件下で接触させ；
上記多孔質樹脂は少なくとも１つのイオン交換官能基、少なくとも１つの親水性極性成分、及び少なくとも１つの疎水性成分を含み；
上記収着した溶質を有する上記多孔質樹脂を上記多孔質樹脂から上記溶質を放出するような条件下で溶媒を用いて洗浄し；そして 上記洗浄の後に、上記溶媒中に存在する上記放出した溶質の量を分析により決定する： ことを含む上記方法。
［４５］
上記多孔質樹脂は化学式Ｉの化合物及びその塩である４４の方法。
［４６］
上記多孔質樹脂はスルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）である４５の方法。
［４７］
開口容器内に詰められた多孔質樹脂を含み、上記多孔質樹脂は少なくとも１つのイオン交換官能基、少なくとも１つの親水性極性成分、及び少なくとも１つの疎水性成分を含む固相抽出カートリッジ。
［４８］
上記多孔質樹脂は化学式Ｉの化合物及びその塩である４７の固相抽出カートリッジ。
［４９］
上記多孔質樹脂はスルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）である４８の固相抽出カートリッジ。
【図面の簡単な説明】
【図１】模範的化合物のアセトアミノフェン、ｐ‐トルアミド、カフェイン、プロカインアミド、ラニチジン、アンフェタミン、メスアンフェタミン及びｍ‐トルイジンの化学式を示す。
【図２】図２Ａは、ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）のバッチ６Ｂに対するクロマトグラフ保持力に基づくイオン強度の効果を示すグラフである。図２Ｂは、スルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）のバッチＪＪＬ０３‐１００に対するクロマトグラフ保持力に基づくイオン強度の効果を示すグラフである。
【図３】本発明の特定のスルホン化樹脂に対する模範的化合物のクロマトグラフ保持力に基づくスルホン化の効果を示すグラフである。
【図４】SymmetryShield（登録商標）ＲＰ8カラムを用いた模範的化合物の分離を示すクロマトグラムである。
【図５】図５Ａは、ラニチジンが内標準である固相抽出のために、スルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）のバッチＪＪＬ０３‐１２４及びバッチＪＪＬ０３‐１００を用いた豚の血漿からのメタノール／水酸化アンモニウム抽出物のクロマトグラムである。図５Ｂは、ラニチジンが内標準である固相抽出のために、スルホン化ポリ（ジビニルベンゼン‐ｃｏ‐Ｎ‐ビニルピロリドン）のバッチＪＪＬ０３‐１２４及びバッチＪＪＬ０３‐１００を用いた豚の血漿からのメタノール／水酸化アンモニウム抽出物のクロマトグラムである。[0001]
Field of Invention
The present invention relates to a novel porous resin for solid phase extraction and chromatography containing at least one hydrophobic component, at least one hydrophilic component and at least one ion exchange functional group.
Background of the Invention
Solid phase extraction (SPE) is a chromatograph widely used, for example, for preconcentration and purification of analytical samples, for purification of various chemicals, and for removing toxic or useful substances from aqueous solutions. Technology. SPE is typically performed using a column or cartridge containing a suitable resin. The SPE method has been developed using absorbents that can interact with the analyte by binding, and separating the analyte from the fluid by hydrophobic, ion exchange, chelation, sorption and other mechanisms. . Depending on the application of SPE, different absorbents are required, and therefore, absorbents with new properties having special selectivity are required.
Summary of the Invention
An object of the present invention is to provide a compound that can be used as a porous resin for solid phase extraction and chromatography, which exhibits excellent wettability.
[0002]
Another object of the present invention is to provide a porous resin compound having special selectivity.
Another object of the present invention is to provide a porous resin compound capable of selectively capturing an analyte and preventing the analyte from passing unretained.
[0003]
Another object of the present invention is to provide a porous resin compound having an ion exchange functional group, a hydrophobic component and a hydrophilic polar component.
Another object of the present invention is to utilize the novel porous resin of the present invention to isolate or remove solutes from solution.
[0004]
Yet another object of the present invention is to utilize the novel porous resin of the present invention to analytically determine the amount of solute in solution.
In one aspect, the present invention provides
Chemical formula:
[0005]
[Chemical 6]
And a salt thereof,
Where the order of A, B and C is random, block, or a combination of random and block;
However,
[0007]
[Chemical 7]
However, A is
[0009]
[Chemical 8]
Selected from the group consisting of
However, B is
[0011]
[Chemical 9]
Selected from the group consisting of
Where C is A or modified A, where modified A is
[0013]
[Chemical Formula 10]
Selected from the group consisting of and
Where X is SOThreeH, CH2CO2H, CH2CH (CO2H)2, CO2H, POThreeH2, PO2H2, CH2POThreeH2, CH2Cl, CH2NH2, CH2N [(CH2)yCHThree]2(Where y is an integer from 0 to 18), CH2N+[(CH2)y =CHThree]ThreeD-(Where y = is an integer from 0 to 18 and D-Is an anion), SO2NHR (where R is polyethyleneimine), and CH2It is selected from the group consisting of NHR (where R is polyethyleneimine).
[0015]
Another aspect of the invention is to copolymerize at least one hydrophobic monomer and at least one hydrophilic monomer to form a copolymer, and to sulfonate the copolymer to at least 1 A porous resin obtained by producing a sulfonated copolymer comprising one ion exchange functional group, at least one hydrophilic component, and at least one hydrophobic component.
[0016]
In a preferred embodiment, the hydrophobic monomer is divinylbenzene, the hydrophilic monomer is N-vinylpyrrolidone, and the copolymer is poly (divinylbenzene-co-N-vinylpyrrolidone). . Preferably, the porous resin is sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone).
[0017]
Another aspect of the present invention is a porous resin for solid phase extraction or chromatography comprising at least one ion exchange functional group, at least one hydrophilic component, and at least one hydrophobic component.
[0018]
Another aspect of the invention is a method of treating a solution to isolate or remove solutes. The solution having a solute comes into contact with the porous resin under conditions such that the solute is sorbed onto the porous resin. The porous resin includes at least one ion exchange functional group, at least one hydrophilic polar component, and at least one hydrophobic component. In certain embodiments, the solute is removed from the porous resin. In certain embodiments, the ion exchange functional group is SO.ThreeH, CH2CO2H, CH2CH (CO2H)2, CO2H, POThreeH2, PO2H2, CH2POThreeH2, CH2Cl, CH2NH2, CH2N [(CH2)yCHThree]2(Where y is an integer from 0 to 18), CH2N+[(CH2)y =CHThree]ThreeD-(Where y = is an integer from 0 to 18 and D-Is an anion), SO2NHR (where R is polyethyleneimine) or CH2NHR (where R is polyethyleneimine). In certain embodiments, the hydrophilic monomer comprises a heterocyclic group, such as a saturated, unsaturated or aromatic heterocyclic group. Examples of nitrogen-containing heterocyclic groups include pyridyl groups, such as 2-vinylpyridine, 3-vinylpyridine, or 4-vinylpyridine, or pyrrolidonyl groups, such as N-vinylpyrrolidone. In certain embodiments, the hydrophobic monomer is an aromatic carbocyclic group, such as a phenyl or phenylene group, or a linear C2-C18-Alkyl groups or branched C2-C18-Contains an alkyl group. The hydrophobic monomer is, for example, styrene or divinylbenzene. A preferred copolymer is poly (divinylbenzene-co-N-vinylpyrrolidone). Preferred porous resins are compounds of formula I and salts thereof. Preferably, the porous resin is sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone).
[0019]
Another feature of the present invention is a method for analytically determining the amount of solute in a solution. The solution having a solute comes into contact with the porous resin under conditions such that the solute sorbs on the porous resin. The porous resin includes at least one ion exchange functional group, at least one hydrophilic polar component, and at least one hydrophobic component. The porous resin having a sorbed solute is washed with a solvent under conditions that release the solute from the porous resin. After washing, the amount of released solute present in the solvent is determined by analysis. In a particular embodiment, the porous resin is a compound of formula I and salts thereof. Preferably, the porous resin is sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone).
[0020]
Another feature of the present invention is a solid phase extraction cartridge containing a porous resin packed in an open container. The porous resin includes at least one ion exchange functional group, at least one hydrophilic polar component, and at least one hydrophobic component. In a particular embodiment, the porous resin is a compound of formula I and salts thereof. Preferably, the porous resin is sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone).
[0021]
The above and other features, objects and advantages of the present invention will be better understood from the following specification in conjunction with the drawings.
Detailed description
The present invention
Chemical formula:
[0022]
Embedded image
And a salt thereof,
Where the order of A, B and C is random, block, or a combination of random and block;
However,
[0024]
Embedded image
However, A is
[0026]
Embedded image
Selected from the group consisting of
However, B is
[0028]
Embedded image
Selected from the group consisting of
Where C is A or modified A, where modified A is
[0030]
Embedded image
Selected from the group consisting of and
Where X is SOThreeH, CH2CO2H, CH2CH (CO2H)2, CO2H, POThreeH2, PO2H2, CH2POThreeH2, CH2Cl, CH2NH2, CH2N [(CH2)yCHThree]2(Where y is an integer from 0 to 18), CH2N+[(CH2)y =CHThree]ThreeD-(Where y = is an integer from 0 to 18 and D-Is an anion), SO2NHR (where R is polyethyleneimine), and CH2It is selected from the group consisting of NHR (where R is polyethyleneimine).
[0032]
Preferred compounds are those where X is SOThreeH, CH2POThreeH2, CH2CO2H or a combination thereof. The most preferred compound is where X is SOThreeH.
[0033]
Preferably, X is present at a concentration of about 0.01 to about 5.0 milliequivalents per gram of compound, more preferably at a concentration of about 0.6 to about 3.2 milliequivalents, even more preferably It is present at a concentration of about 0.8 to about 2.1 milliequivalents, and most preferably at a concentration of about 1.0 milliequivalents.
[0034]
The order of blocks means the order in which the constituent units are combined in a fixed pattern or a series of repetitions. Random order means the order in which each constituent unit is randomly combined.
[0035]
The compounds of the present invention contain at least one hydrophobic monomer, such as divinylbenzene, styrene, or ethylvinylbenzene, and at least one hydrophilic monomer, such as N-vinylpyrrolidone, N-vinylpyridine, methacrylate, It can be prepared by functionalizing, i.e. chemically changing, methyl methacrylate, vinyl acetate, acrylamide or methacrylamide. Preferably, the hydrophobic monomer is divinylbenzene. Preferably, the hydrophilic monomer is N-vinyl pyrrolidone. The copolymer can be prepared by standard synthetic methods known to those skilled in the art, for example, as described in Example 1.
[0036]
Such copolymers, such as poly (divinylbenzene-co-N-vinylpyrrolidone), can be functionalized by the addition of ion exchange functional groups, X groups, which groups are cations such as SOThreeH, CH2CO2H, CH2CH (CO2H)2, CO2H, POThreeH2, PO2H2Or CH2POThreeH2Or an anion such as CH2NH2, CH2N [(CH2)yCHThree]2, CH2N+[(CH2)y =CHThree]ThreeD-, SO2NHR or CH2NHR or intermediates such as CH2Cl. These additions are described, for example, by Lieto et al., Chemtech, p. 46-53 (1983); Mitchell et al., Tetrahedron Letters, p. 3795-3798 (1976); Can be achieved as described in “Unpacking and stationary phases in chromatographic technology” by K. Unger. See, for example, Example 2, which describes the sulfonation of poly (divinylbenzene-co-N-vinylpyrrolidone).
[0037]
The novel compound of the present invention can be used, for example, as a porous resin for solid phase extraction and chromatography. Solid phase extraction isolates a class of molecular species from fluid phases such as gases and liquids by, for example, sorption, ion exchange, chelation, size exclusion (molecular filtration), affinity, or ion pair mechanisms. Therefore, it means a method of employing a solid phase.
[0038]
The present invention also provides a copolymer formed by copolymerizing at least one hydrophobic monomer and at least one hydrophilic monomer, and the copolymer is sulfonated to produce at least one ion-exchange functional group. A porous resin obtained by forming a sulfonated copolymer comprising at least one hydrophobic component and at least one hydrophilic component.
[0039]
Porous resin refers to a member of a class of crosslinked polymer particles that penetrates through channels through which solutions can diffuse. Pore means the area between closely packed polymer chains. Monomer means a molecule or polymer repeating unit containing one or more polymerizable functional groups prior to polymerization. Copolymer means a polymer comprising two or more different monomers. An ion exchange functional group means a group in which the counter ion is partially free and can be easily exchanged for another ion of the same sign. Hydrophilic means having an affinity to attract, adsorb or absorb water. Hydrophobic means having no affinity to repel water or to adsorb or absorb water.
[0040]
In a preferred embodiment, the hydrophobic monomer is divinylbenzene. In a preferred embodiment, the hydrophilic monomer is N-vinyl pyrrolidone. In a preferred embodiment, the copolymer is poly (divinylbenzene-co-N-vinylpyrrolidone). In a preferred embodiment, the porous resin is sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone). Preferably, the sulfonate group is from about 0.01 to about 5.0, more preferably from about 0.6 to about 3.2, and even more preferably from about 0.8 to about 2.1 per gram of porous resin. And most preferably at a concentration of about 1.0 milliequivalent.
[0041]
The invention also includes a porous resin for solid phase extraction or chromatography containing at least one ion exchange functional group, at least one hydrophilic component, and at least one hydrophobic component.
[0042]
The ion exchange functional group can allow the porous resin to interact with the basic cation solute. The hydrophilic polar component can make the porous resin have polar interaction with the solute and hydrogen bonding ability. The hydrophobic component can give the porous resin an affinity for nonpolar solutes through hydrophobic interactions. Since the porous resin of the present invention has a combination of various interaction forces with respect to the solute, these are extremely useful resins in, for example, solid phase extraction, ion exchange, and liquid chromatography. For example, these novel porous resins can recover, fix and / or remove solutes from fluids.
[0043]
The invention also includes a method of treating a solution to isolate or remove a solute. The solution having a solute contacts the porous resin under conditions such that the solute is sorbed onto the porous resin. The porous resin includes at least one ion exchange functional group, at least one hydrophilic component, and at least one hydrophobic component. In some embodiments, the solute is removed from the porous resin.
[0044]
Sorption means that it can be taken up and retained by absorption or adsorption.
In some embodiments, the ion exchange functional group is SO.ThreeH, CH2CO2H, CH2CH (CO2H)2, CO2H, POThreeH2, PO2H2, CH2POThreeH2, CH2Cl, CH2NH2, CH2N [(CH2)yCHThree]2(Where y is an integer from 0 to 18), CH2N+[(CH2)y =CHThree]ThreeD-(Where y = is an integer from 0 to 18 and D-Is an anion), SO2NHR (where R is polyethyleneimine) or CH2NHR (where R is polyethyleneimine). Preferably, the ion exchange functional group is SO.ThreeH. Preferably, the ion exchange functional groups are from about 0.01 to about 5.0, more preferably from about 0.6 to about 3.2, and even more preferably from about 0.8 to about 2. per gram of porous resin. 1, and most preferably at a concentration of about 1.0 milliequivalent.
[0045]
In some embodiments, the hydrophilic polar component is an amide group, ester group, carbonate group, carbamate group, urea group, hydroxy group, or pyridyl group.
In certain embodiments, the porous resin comprises a copolymer having at least one ion exchange functional group, and the copolymer comprises at least one hydrophilic monomer and at least one hydrophobic monomer. Preferably, the hydrophilic monomer comprises a heterocyclic group, such as a saturated, unsaturated or aromatic heterocyclic group. Examples include nitrogen-containing heterocyclic groups such as pyridyl groups such as 2-vinyl pyridine, 3-vinyl pyridine, or 4-vinyl pyridine, or pyrrolidonyl groups such as N-vinyl pyrrolidone. Preferably, the hydrophobic monomer is an aromatic carbocyclic group, such as a phenyl group or a phenylene group, or a linear C2-C18-Alkyl groups or branched C2-C18-Contains an alkyl group. The hydrophobic monomer is, for example, styrene or divinylbenzene. A preferred copolymer is poly (divinylbenzene-co-N-vinylpyrrolidone).
[0046]
Preferred porous resins are the compounds of formula I described above and salts thereof. Preferably, the porous resin is sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone).
[0047]
In a preferred embodiment, the porous resin comprises at least about 12 mole percent N-vinyl pyrrolidone. In a preferred embodiment, the porous resin contains less than about 30 mole percent N-vinyl pyrrolidone. The mole percentage means the mole fraction, expressed as a percentage, of the monomer of interest relative to the total moles of the various (two or more) monomers that make up the copolymer of the porous resin. Preferably, the porous resin has a solid phase extraction capability.
[0048]
The porous resin may be, for example, beads, pellets, or other shapes depending on the application. The porous resin particles can have, for example, a spherical shape, a regular shape, or an irregular shape. Preferably, the resin particles are beads having a diameter in the range of about 3 to about 500 μm, more preferably about 20 to about 200 μm. Preferably, the porous resin has a specific surface area in the range of about 50 to about 850 square meters per gram and a diameter in the range of about 0.5 nm to about 100 nm. In some embodiments, the porous resin is placed in a matrix.
[0049]
In some embodiments, more than one type of functionalized porous resin can be used in the columns, cartridges and the like of the present invention.
A solute can be, for example, a molecule having hydrophobic, hydrophilic, or ionic interactions or a combination of two or three of these interactions. Preferably, the solute is an organic compound having a polarity suitable for being adsorbed on the porous resin. Such solutes are, for example, burning of chemicals, pesticides, herbicides, poisons and environmental pollutants such as underground fuels or other industrial materials such as metal-organic compounds including heavy metals such as mercury, lead or cadmium. Including substances produced by The solute may be a metabolite or decomposition product of the above substance. Solutes include, for example, proteins, peptides, hormones, polynucleotides, vitamins, cofactors, metabolites, biomolecules such as lipids, and carbohydrates.
[0050]
The solution can include, for example, water, an aqueous solution, water or a mixture of aqueous solutions, and a water-miscible polar organic solvent such as methanol, ethanol, N, N-dimethylformamide, dimethyl sulfoxide or acetonitrile. In preferred embodiments, the solution is an acidic, basic or neutral aqueous solution, i.e., a solution having a volume of about 1% to about 99% water. The solution containing the solute can optionally further comprise one or more other solutes. In certain embodiments, the solution is an aqueous solution containing complexes of various solutes. This type of solution includes, for example, blood, plasma, urine, spinal fluid, synovial fluid, and other biological fluids including extracts of tissues such as liver tissue, muscle tissue, brain tissue or heart tissue. These extracts may be, for example, aqueous or organic extracts, which are returned to water or water / organic mixtures after drying. Solutions also include aqueous or organic extracts of environmental samples such as ground water, ground water, drinking water, or soil samples. Other examples of solutions include foods such as fruit or vegetable juices or milk, or aqueous or aqueous / organic extracts of foods such as fruits, vegetables, grains or meat. Other solutions include, for example, natural extracts from plants and soups.
[0051]
The solution can be contacted with the porous resin by a method of sorbing the solute onto the porous resin, such as batch or chromatographic methods. For example, the solution may be passed through a porous polymer column, disk or plug, or the solution may be stirred with the porous resin in a batch-stirred reactor. The solution may also be added to a porous resin-containing well consisting of a microtiter plate. The porous resin can also be in the form of beads or pellets, for example. The solution contacts the porous resin for a time sufficient for the solute to substantially sorb onto the porous resin. This time is the time required for the solute to equilibrate between the porous resin surface and the solution. Sorption or partitioning of the solute onto the porous resin is partial or complete.
[0052]
In some embodiments, the porous resin is filled as particles in an open container to form a solid phase extraction cartridge.
The invention also includes a method for analytically determining the amount of solute in a solution. The solution having the solute contacts the porous resin under conditions that allow sorption of the solute to the porous resin. The porous resin includes at least one ion exchange functional group, at least one hydrophilic polar component, and at least one hydrophobic component. The porous resin having the sorbed solute is washed with a solvent under conditions that release the solute from the porous resin. After the washing, the amount of the released solute present in the solvent is determined by analysis.
[0053]
In some embodiments, the porous resin is a compound of formula I and salts thereof. Preferably, the porous resin is sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone).
[0054]
The solution in contact with the porous resin can contain the solute of interest in diluted form, for example, at a concentration that is too low for accurate quantification. The solute is sorbed onto the porous resin and then desorbed using, for example, a substantially small volume of a less polar solvent, thereby containing the desired solute and having a substantially higher concentration of solute than the initial solution. High solution can be prepared. This method allows for solvent exchange, that is, the solvent can be removed from the first solvent and redissolved in the second solvent.
[0055]
Suitable solvents for desorbing solutes from porous resins are polar water-miscible organic solvents such as alcohols such as methanol, ethanol, isopropanol, or acetonitrile, acetone, tetrahydrofuran, or water and mixtures of these solvents. is there. The desorption solvent is also a nonpolar or moderately polar water-immiscible solvent such as, for example, dichloromethane, diethyl ether, chloroform, or ethyl acetate. Mixtures of these solvents are also suitable. The preferred solvent or solvent mixture should be determined for each separate case. Preferred solvents are routinely used in chromatographic methods and can be determined by one skilled in the art without undue experimentation (eg, McDonald and Bouvier, eds., Application guides and references for solid phase extraction). (See "Resources for Advances in Sample Preparation",
[0056]
The amount of desorbed solvent present in the solvent can be analytically determined by various techniques known to those skilled in the art, such as high performance liquid chromatography, gas chromatography, gas chromatography / mass spectrometry, or immunoassay. .
[0057]
The present invention also includes a solid-phase extraction cartridge containing a porous resin packed in an open container. The porous resin includes at least one ion exchange functional group, at least one hydrophilic polar component, and at least one hydrophobic component. In a particular embodiment, the porous resin is a compound of formula I as described above and salts thereof. Preferably, the porous resin is sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone).
[0058]
The container is, for example, a cylindrical container or column open at both ends, where the solution enters the container through one end, contacts the porous resin in the container, and exits the container through the other end. The porous resin can be filled into the container as small particles such as beads having a diameter of about 3 μm to about 500 μm, preferably about 20 μm to about 200 μm. In one embodiment, the porous resin particles can be filled in the container in a state where the porous resin particles are put on the net of the porous membrane.
[0059]
The container can be formed from a material that is compatible with the solution and solvent used in the process within the time frame of the solid phase extraction process. Such materials include glass or various plastics such as high density polyethylene and polypropylene. In some embodiments, the container is largely cylindrical and has a narrow tip at one end. An example of such a container is a syringe barrel. The amount of porous resin in the container is limited by the volume of the container and is in the range of about 0.001 grams to about 50 kilograms, preferably about 0.025 grams to about 1 gram. The amount of porous resin suitable for the desired extraction depends on the amount of solute sorbed, the surface area utilized of the porous resin, and the strength of the interaction between the solute and the porous resin. This amount can be readily determined by one skilled in the art. The cartridge is a single use cartridge that may be discarded after being used to process a single sample or may be used to process multiple samples.
[0060]
The following non-limiting examples further illustrate the present invention.
Example
Example 1:Poly (divinylbenzene-co-N-vinylpyrrolidone) copolymerization
Preparation of
This example illustrates the preparation of poly (divinylbenzene-co-N-vinylpyrrolidone) copolymer.
[0061]
A solution of 5.0 grams of hydroxypropyl methylcellulose (Methocel E15, Dow Chemical Company, Midland, MI) in 1000 milliliters of water was added to a 3000 milliliter flask. This includes 175 grams of divinylbenzene (DVB HP-80, Dow Chemical), 102 grams of N-vinyl-2-pyrrolidone (International Specialty Products, Wayne, NJ), and 1.85 grams of azobisisobutyronitrile. (Vazo 64, DuPont Chemical Company, Wilmington, Del.) Was added to a solution of 242 grams of toluene.
[0062]
The 80% purity divinylbenzene may be replaced with other hydrophobic monomers such as styrene or ethylvinylbenzene, or low purity divinylbenzene, but 80% purity divinylbenzene is preferred. The N-vinyl pyrrolidone may be substituted with other hydrophilic monomers such as N-vinyl-pyridine, methacrylate, methyl methacrylate, vinyl acetate, acrylamide, or methacrylamide, but N-vinyl pyrrolidone is preferred .
[0063]
The resulting biphasic mixture was stirred at room temperature for 30 minutes to form the desired micron sized oil droplets. The resulting suspension was then heated to 70 ° C. with moderate stirring and maintained at this temperature for 20 hours. The suspension was cooled to room temperature, filtered and washed with methanol. The filter cake was dried in vacuo at 80 ° C. for 16 hours. The composition of the product polymer was determined by elemental analysis. Elemental analysis: N: 2.24%; mole percent N-vinylpyrrolidone: 20%.
[0064]
Also, by varying the starting ratio of divinylbenzene and N-vinylpyrrolidone by this method, a series of poly (divinylbenzene-co-N-vinyl containing about 13, 14, 16, and 22 mole percent N-vinylpyrrolidone. A pyrrolidone) copolymer was prepared.
Example 2:Poly (divinylbenzene-co-N-vinylpyrrolidone) copolymerization
Sulfonation
This example illustrates the preparation of a sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone) porous resin. The copolymer obtained from Example 1, preferably poly (divinylbenzene-co-N-vinylpyrrolidone), is derivatized with sulfuric acid (95-98%, ACS reagent, Aldrich, 25,810-5, Milwaukee, Wis.). it can. Most preferably, OASIS® HLB (available from Waters Inc., Milford, Mass.) Is used.
[0065]
Can serve as a guide for process design and quality control.
Formula 1: Copolymer (meq HSOThree/ G sulfonated copolymer) ion
Exchange capacity = 0.53 + 0.018 × [temperature] +0.00029
× [Time]
Where [temperature] = reaction temperature (° C.)
[Time] = Reaction time (minutes)
[0066]
[Table 1]
Example 3:Of sulfonation on chromatographic retention behavior of sulfonated resin
effect
This example shows how the degree of sulfonation of sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone) resin affects the hydrophobic and ion exchange behavior of the resin and the retention properties of the resin .
[0068]
The resins JJL03-90, 100, 114, 119, 123, 124, and 143 obtained from Example 2 were each loaded into a 4.6 × 30 mm high-performance liquid chromatography (HPLC) column as a slurry. The effect of sulfonation on hydrophobic retention and ion exchange behavior was determined by examining the retention of various neutral and basic analytes. Model compounds selected were acetaminophen, p-toluamide, caffeine, procainamide, ranitidine, amphetamine, methamphetamine and m-toluidine. These model compounds are shown in FIG. The mobile phase is 40:60 methanol-20 mM (NHFour) H2POFourComposed of NHFourThe pH was adjusted to 3.0 using Cl as an ionic strength regulator. The flow rate was 1.0 mL / min and the temperature was 30 ° C. The injection volume was 5 microliters. Each compound was injected separately. Detection was performed with 254 nm UV light.
[0069]
Retention behavior was determined as a function of ionic strength to determine if there was an interaction due to a hydrophobic or ionic mechanism. FIGS. 2A and 2B show non-sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone) (Oasis® HLB, batch 6B) and relatively sulfonated poly (divinylbenzene-co-N-vinyl). Pyrrolidone) (Batch JJL03-100) (2.52 meq / g) shows the effect of ionic strength based on retention. As can be seen from the non-sulfonated resin, with increasing ionic strength, there was very little increase in retention for all components. This result is consistent with the mechanism of hydrophobic interaction. For non-sulfonated resins, when the retention coefficient was-<1, the hydrophobic retention of the basic compound was only slight under the conditions used. In the case of the sulfonated resin, it has been found that the retention of the neutral compound hardly changes. However, the retention of basic compounds was dramatically affected by ionic strength. Holding power increases significantly with increasing ionic strength, suggesting an ion exchange mechanism.
[0070]
FIG. 3 shows the effect of sulfonation of the resin based on holding power. 1M NHFourCl was used to minimize the retention time. This graph shows that the retention of neutral compounds decreased with increasing sulfonation. For basic compounds, retention increased as sulfonation increased to 1 meq / g. However, at higher levels of sulfonation, the holding power decreased again.
Example 4:Effect of sulfonation based on the implementation of solid phase extraction of sulfonated resin
This example illustrates the effect of sulfonation of this resin based on performing solid phase extraction (SPE) of the sulfonated resin.
[0071]
In order to evaluate the performance of SPE, an HPLC method was employed to verify the recovery of several model compounds. A SymmetryShield® RP8 column, 3.5 μm, 4.6 × 75 mm (Waters Inc., Milford, Mass.) Was used inline with a Sentry® column (Waters Inc., Milford, Mass.). The flow rate was 2.0 ml / min and the temperature was 36 ° C. The mobile phase is 95: 5 20 mM K.2HPOFourPH 7.0-Methanol. Detection was performed with 254 nm UV light. The injection volume was 10 μL. A chromatogram showing optimal separation is shown in FIG.
[0072]
The following resins were used for SPE evaluation: Oasis® HLB batch # 6B, JJL03-143, JJL03-124 and JJL03-100. SPE was performed using 30 milligrams of absorbent each in 96-well plate form. The process is as follows. The cartridge / well was conditioned with 1 milliliter of methanol (-1 mL / min) and then equilibrated with 1 milliliter of water. A 1 milliliter sample consisting of spiked phosphate buffered saline or spiked porcine plasma was introduced. Samples were spiked with acetaminophen, toluamide, caffeine and procainamide to 10 μg / mL and with amphetamine, mesamphetamine and toluidine to 20 μg / mL. The introduced sample is washed with water containing 1 ml of 0.1 M HCl, then with 1 ml of methanol, and 2% NH.FourElute with 1/2 of 1 ml methanol containing OH. All fractions were collected after equilibration. 50 μL of 10 μg / mL ranitidine was added to each sample. This sample is placed in the heating block with N2Evaporated to dryness under a stream. The sample was then reconstituted with 1 milliliter of 20 mM phosphate buffer (pH 7.0).
[0073]
Initial SPE performance experiments were performed in phosphate-buffered saline. A complete mass balance was performed on the SPE fraction using sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone), batch # JJL03-143. Table 2 shows the results of recovery and mass balance.
[0074]
[Table 2]
Amphetamine, mesamphetamine and toluidine were not fully recovered in all cases. This is due to the fact that these compounds are semi-volatile and are lost through evaporation. In the experimental example where the sample was not dry, complete recovery was obtained. Saline was collected and examined, and no leakage occurred in the addition or HCl wash step in any case. All compounds eluted in a methanol wash against Oasis® HLB, but only neutral compounds eluted on all sulfonated resins. Basic compound is methanol / NHFourEluted completely with OH solution. For the sulfonated resin, most of the caffeine eluted with the first methanol wash. It was also found that the recovery of each fraction depends on the degree of sulfonation, and that the resin with minimal sulfonation has the maximum recovery after the first methanol wash. This unusual result is a pK of 13.9 caffeine.bThis is due to the fact that it is a weak base. According to another observation, acetaminophen showed a slight amount of leakage (-1%) in the methanol / base elution with respect to the sulfonated resin.
[0076]
Similar results were obtained when using plasma. Table 3 shows the recovery results obtained for Oasis® HLB batches 6B, JJL03-100 and JJL03-124 for three different absorbents.
[0077]
[Table 3]
Neutral material eluted in the methanol wash and base eluted in the methanol / ammonium hydroxide step. HPLC analysis of the unspiked plasma extract from the sulfonated resin is shown in FIGS. 5A and 5B, where ranitidine is the internal standard.
[0080]
The protein in the extract was weighed with Coomassie blue. Two different lots of plasma were tested. The results are shown in Table 4.
[0081]
[Table 4]
The protein in basified methanol was found to be similar for Oasis® HLB, JJL03-100 and JJL03-124. As a comparison, for Oasis® HLB cartridges (from the methanol elution step), these protein masses are the recommended SPE protocol (“Water Oasis® HLB extraction cartridges and plates” 1997 Waters Inc., 6 / 97WB025-US) about 5 times less than what is typically observed.
[0083]
At high sulfonated loadings, the plasma load through the resin was suspended. Related observations have shown that the flow rate decreases at high sulfonation loading. These observations result from the acidity of the resin. Most sulfonated resins have the highest acidity. Thus, passing plasma through the resin corresponds to the formation of an acidic precipitate, which makes the sample more suspended and plugs the frit and resin-containing packed bed.
Example 5:Poly (divinylbenzene-co-N-vinylpyrrolidone) porous
Chloromethylation of resin
Poly (divinylbenzene-co-N-vinylpyrrolidone), OASIS® HLB (Waters, Inc., Milford, Mass.) With hydrochloric acid (12 mol, 36.5-38%, ACS reagent, JTBaker, 9535) -03, Phillipsburgh, NJ) and paraformaldehyde (95%, Aldrich Chemical, 15,812-7, Milwaukee, WI). A 3 liter three-necked round bottom flask was equipped with a thermometer, stirrer, condenser, and reactor temperature controller. Hydrochloric acid was introduced into the flask (see Table 5 for the amount of hydrochloric acid). Stirring and temperature control were then performed. The stirrer was fixed by a ground glass shaft through a suitable Teflon bearing in the central opening at the top of the flask. The Teflon paddle was a single blade. The stirring speed was adjusted to obtain proper mixing. Poly (divinylbenzene-co-N-vinylpyrrolidone), OASIS® HLB was added (see Table 5 for the amount of OASIS® HLB). Paraformaldehyde was then added (see Table 5 for the amount of paraformaldehyde). The reaction mixture was stirred for a specified time at a constant temperature (see Table 5 for reaction time and temperature). The reaction mixture was cooled and the acid solution was filtered. Chloromethylated poly (divinylbenzene-co-N-vinylpyrrolidone) copolymer was collected and washed with water until the pH of the slurry was above 5.0. The filter cake of the chloromethylated poly (divinylbenzene-co-N-vinylpyrrolidone) copolymer was then washed twice with methanol (HPLC grade, JT Baker, 9535-03, Phillipsburgh, NJ) and in vacuo It dried at 80 degreeC for 15 hours. The degree of chloromethylation was determined by elemental chlorine analysis (Atlantic Microlab, Inc., Norcross, GA). Chloromethyl group (CH2The amount of Cl) is shown in Table 5.
[0084]
It has been found that the reaction time, reaction temperature, and molar concentration of hydrochloric acid all affect the amount of chloromethyl group imparted to the poly (divinylbenzene-co-N-vinylpyrrolidone) copolymer. Various combinations of these three variables and the resulting chloromethyl levels are shown in Table 5.
[0085]
[Table 5]
Example 6:Chloromethylated poly (divinylbenzene-co-N-vinylpyro
Lydon) Amination of porous resin
A chloromethylated poly (divinylbenzene-co-N-vinylpyrrolidone) porous resin prepared as described in Example 5 was converted to the following tertiary amines (all purchased from Aldrich Chemical, Milwaukee, Wis.): Trimethylamine (TMA, 40 wt% aqueous solution, 43, 326-8), triethylamine (TEA, 99%, 13, 206-3), N, N-dimethylethylamine (DMEA, 99%, 23, 935-6), N , N-diethylmethylamine (DEMA, 98%, D9, 820-3), N, N-dimethylbutylamine (DMBA, 99%, 36, 952-7), and N-methylpyrrolidone (NMP, 97%, M7) , 920-4). A general amination procedure is shown below. The chloromethylation load and steric size of reactive amine alkyl groups (Hirsch, JA, Topics in Stereochemistry, Volume 1, Allinger, NL; Eliel, ED, Eds. Wiley: New York, 1967, Chapter 1) It has been found that it normally affects the loading of ammonium groups onto the (divinylbenzene-co-N-vinylpyrrolidone) copolymer. The general reaction procedure is shown below. Various combinations of Step 1 chloromethyl loading, amine type, and reaction temperature, and the resulting quaternary amine loading are shown in Table 6.
[0087]
A 250 ml three-necked round bottom flask was equipped with a thermometer, stirrer, condenser, and reactor temperature controller. Trialkylamine was introduced into the flask (see Table 6 for the amount of each amine) and stirring and temperature control were started. The stirrer was fixed by a ground glass shaft through a suitable Teflon bearing in the central opening at the top of the flask. The Teflon paddle was a single blade. Chloromethylated poly (divinylbenzene-co-N-vinylpyrrolidone) was added (see Table 6 for resin amounts) and the stirring speed was adjusted to obtain sufficient mixing. The reaction mixture was stirred for a certain time at a constant temperature (see Table 6 for reaction time and temperature). The reaction mixture was cooled and the amine was filtered. The aminated poly (divinylbenzene-co-N-vinylpyrrolidone) copolymer was collected and washed with water until the pH of the slurry was below 5.5. The filter cake of the aminated poly (divinylbenzene-co-N-vinylpyrrolidone) copolymer was then washed twice with methanol (HPLC grade, JT Baker, 9535-03, Phillipsburgh, NJ) and 80% in vacuo. Dry at 15 ° C. for 15 hours. The degree of amination was determined by titration. Methylenetrialkylammonium group (CH2NRThree +Cl-) Is shown in Table 6.
[0088]
[Table 6]
In conclusion, the above experiments demonstrated that sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone) can be used in a conventional manner for SPE of basic compounds. It can also be used as a tool to achieve class separation of neutral and basic compounds.
[0090]
Those skilled in the art will be able to ascertain many equivalents of the above-described embodiments of the present invention using only routine experimentation. These and all equivalents are within the protection scope of the above-mentioned claims.
[Aspect of the Invention]
[1]
Chemical formula:
[Chemical 1]
However,
[Chemical 2]
[Chemical Formula 3]
Where B is
[Formula 4]
[Chemical formula 5]
Where X is SO Three H, CH 2 CO 2 H, CH 2 CH (CO 2 H) 2 , CO 2 H, PO Three H 2 , PO 2 H 2 , CH 2 PO Three H 2 , CH 2 Cl, CH 2 NH 2 , CH 2 N [(CH 2 ) y CH Three ] 2 (Where y is an integer from 0 to 18), CH 2 N + [(CH 2 ) y = CH Three ] Three D - (Where y = is an integer from 0 to 18 and D - Is an anion), SO 2 NHR (where R is polyethyleneimine), and CH 2 The above compounds selected from the group consisting of NHR (where R is polyethyleneimine) and salts thereof.
[2]
X is one compound present at a concentration of about 0.1 to about 5.0 milliequivalents per gram of compound.
[3]
X is one compound present at a concentration of about 0.6 to about 3.2 milliequivalents per gram of compound.
[4]
X is one compound present at a concentration of about 0.8 to about 2.1 milliequivalents per gram of compound.
[5]
X is one compound present at a concentration of about 1.0 milliequivalent per gram of compound.
[6]
X is SO Three H, CH 2 PO Three H 2 And CH 2 CO 2 1 compound selected from the group consisting of H.
[7]
X is SO Three 6. The compound of 6, which is H.
[8]
At least one hydrophobic monomer and at least one hydrophilic monomer are copolymerized to form a copolymer, and the copolymer is sulfonated to form at least one ion exchange functional group, at least A porous resin for solid phase extraction or chromatography obtained by producing a sulfonated copolymer comprising one hydrophilic component and at least one hydrophobic component.
[9]
8. The porous resin according to 8, wherein the hydrophobic monomer is divinylbenzene.
[10]
8. The porous resin according to 8, wherein the hydrophilic monomer is N-vinylpyrrolidone.
[11]
8. The porous resin according to 8, wherein the copolymer is poly (divinylbenzene-co-N-vinylpyrrolidone).
[12]
8. The porous resin according to 8, wherein the porous resin is sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone).
[13]
The sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone) comprises 12 porous resins having sulfonate groups present at a concentration of about 0.1 to about 5.0 milliequivalents per gram of porous resin. .
[14]
A porous resin for solid phase extraction or chromatography comprising at least one ion exchange functional group, at least one hydrophilic component, and at least one hydrophobic component.
[15]
Treating a solution to isolate or remove a solute comprising contacting a solution having a solute with a porous resin under conditions such that the solute sorbs to the porous resin;
The porous resin comprises at least one ion exchange functional group, at least one hydrophilic polar component, and at least one hydrophobic component.
[16]
The ion exchange functional group is SO Three H, CH 2 CO 2 H, CH 2 CH (CO 2 H) 2 , CO 2 H, PO Three H 2 , PO 2 H 2 , CH 2 PO Three H 2 , CH 2 Cl, CH 2 NH 2 , CH 2 N [(CH 2 ) y CH Three ] 2 (Where y is an integer from 0 to 18), CH 2 N + [(CH 2 ) y = CH Three ] Three D - (Where y = is an integer from 0 to 18 and D - Is an anion), SO 2 NHR (where R is polyethyleneimine), and CH 2 14 methods selected from the group consisting of NHR, wherein R is polyethyleneimine.
[17]
The ion exchange functional group is SO Three H, CH 2 PO Three H 2 And CH 2 CO 2 16 methods selected from the group consisting of H.
[18]
The ion exchange functional group is SO Three 17 methods which are H.
[19]
15. The method of 15, wherein the ion exchange functional group is present at a concentration of about 0.1 to about 5.0 milliequivalents per gram of porous resin.
[20]
15. The method according to 15, wherein the hydrophilic polar component is selected from the group consisting of an amide group, an ester group, a carbonate group, a carbamate group, a urea group, a hydroxy group, and a pyridyl group.
[21]
15. The fifteen methods, wherein the porous resin comprises a copolymer having at least one ion exchange functional group, and the copolymer comprises at least one hydrophilic monomer and at least one hydrophobic monomer.
[22]
21. The method according to 21, wherein the hydrophilic monomer contains a heterocyclic group.
[23]
22. The method according to 22, wherein the heterocyclic group is a pyridyl group or a pyrrolidonyl group.
[24]
23. The method according to 23, wherein the pyridyl group is selected from the group consisting of 2-vinylpyridine, 3-vinylpyridine, and 4-vinylpyridine.
[25]
23 methods wherein the pyrrolidonyl group is N-vinylpyrrolidone.
[26]
The hydrophobic monomer is phenyl group, phenylene group, linear C 2 -C 18 -Alkyl groups and branched C 2 -C 18 21 methods comprising a group selected from the group consisting of alkyl groups.
[27]
26. The method according to 26, wherein the hydrophobic monomer is styrene or divinylbenzene.
[28]
26. The method according to 26, wherein the hydrophobic monomer is divinylbenzene.
[29]
21. The method of 21, wherein the copolymer is poly (divinylbenzene-co-N-vinylpyrrolidone).
[30]
15. The method according to 15, wherein the porous resin is a compound of formula I and salts thereof.
[31]
15. The method of 15, wherein the porous resin is sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone).
[32]
31. The method of 31, wherein the sulfonate group is present at a concentration of about 0.1 to about 5.0 milliequivalents per gram of porous resin.
[33]
31. The method of 31, wherein the porous resin comprises at least about 12 mole percent N-vinyl pyrrolidone.
[34]
31. The method of 31, wherein the porous resin comprises less than about 30 mole percent N-vinyl pyrrolidone.
[35]
15. The method according to 15, wherein the porous resin is in the form of beads.
[36]
35. The 35 methods, wherein the beads have an average size of about 3 to about 500 micrometers.
[37]
15. The method according to 15, wherein the porous resin is placed in a matrix.
[38]
15. The method according to 15, wherein the porous resin has a solid-phase extraction capability.
[39]
15. The method according to claim 15, wherein the solute is selected from the group consisting of drugs, agricultural chemicals, herbicides, biomolecules, poisons, pollutants, metabolites, and degradation products thereof.
[40]
15. The method of claim 15, wherein the solution is selected from the group consisting of water, an aqueous solution, water or a mixture of aqueous solutions, and a water-miscible polar organic solvent.
[41]
The solution consists of blood, plasma, urine, cerebrospinal fluid, synovial fluid, tissue extract, ground water, ground water, drinking water, soil extract, food material, food material extract, natural extract from plants and bouillon 15 methods selected from a group.
[42]
15. The method according to 15, wherein the porous resin is in an open container.
[43]
15. The method according to 15, further comprising the step of removing the solute from the porous resin.
[44]
A method for analytically determining the amount of a solute in a solution, wherein the solution having the solute is brought into contact with the porous resin under conditions such that the solute sorbs on the porous resin;
The porous resin comprises at least one ion exchange functional group, at least one hydrophilic polar component, and at least one hydrophobic component;
Washing the porous resin having the sorbed solute with a solvent under conditions that release the solute from the porous resin; and after the washing, the released solute present in the solvent. The above method comprising: determining the amount of by analysis.
[45]
44. The method according to 44, wherein the porous resin is a compound of formula I and salts thereof.
[46]
45. The method according to 45, wherein the porous resin is sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone).
[47]
A solid phase extraction cartridge comprising a porous resin packed in an open container, the porous resin comprising at least one ion exchange functional group, at least one hydrophilic polar component, and at least one hydrophobic component.
[48]
47. The solid phase extraction cartridge according to 47, wherein the porous resin is a compound of formula I and salts thereof.
[49]
48. A solid phase extraction cartridge according to claim 48, wherein the porous resin is sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone).
[Brief description of the drawings]
FIG. 1 shows the chemical formulas of exemplary compounds acetaminophen, p-toluamide, caffeine, procainamide, ranitidine, amphetamine, mesamphetamine and m-toluidine.
FIG. 2A is a graph showing the effect of ionic strength based on chromatographic retention on batch 6B of poly (divinylbenzene-co-N-vinylpyrrolidone). FIG. 2B shows a batch of sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone).JJL03-100It is a graph which shows the effect of the ionic strength based on the chromatographic holding power with respect to.
FIG. 3 is a graph showing the effect of sulfonation based on chromatographic retention of exemplary compounds for certain sulfonated resins of the present invention.
FIG. 4
FIG. 5A shows pigs using batch JJL03-124 and batch JJL03-100 of sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone) for solid phase extraction where ranitidine is the internal standard. Figure 2 is a chromatogram of methanol / ammonium hydroxide extract from plasma. FIG. 5B shows methanol from swine plasma using sulfonated poly (divinylbenzene-co-N-vinylpyrrolidone) batch JJL03-124 and batch JJL03-100 for solid phase extraction with ranitidine as internal standard. / Chromatogram of ammonium hydroxide extract.
Claims (37)
但し、
However,
上記多孔質樹脂は少なくとも１つのイオン交換官能基、少なくとも１つの親水性極性成分、及び少なくとも１つの疎水性成分を含み、そして上記多孔質樹脂が請求項１に記載の化合物又はその塩を含む： 上記方法。Treating a solution to isolate or remove a solute comprising contacting a solution having a solute with a porous resin under conditions such that the solute sorbs to the porous resin;
The porous resin comprises at least one ion exchange functional group, at least one hydrophilic polar component, and at least one hydrophobic component, and the porous resin comprises the compound of claim 1 or a salt thereof: The above method.
上記多孔質樹脂は少なくとも１つのイオン交換官能基、少なくとも１つの親水性極性成分、及び少なくとも１つの疎水性成分を含み、そして上記多孔質樹脂が請求項１に記載の化合物又はその塩を含み；
上記収着した溶質を有する上記多孔質樹脂を上記多孔質樹脂から上記溶質を放出するような条件下で溶媒を用いて洗浄し；そして 上記洗浄の後に、上記溶媒中に存在する上記放出した溶質の量を分析により決定する： ことを含む上記方法。A method for analytically determining the amount of a solute in a solution, wherein the solution having the solute is brought into contact with the porous resin under conditions such that the solute sorbs on the porous resin;
The porous resin comprises at least one ion exchange functional group, at least one hydrophilic polar component, and at least one hydrophobic component, and the porous resin comprises the compound of claim 1 or a salt thereof;
Washing the porous resin having the sorbed solute with a solvent under conditions that release the solute from the porous resin; and after the washing, the released solute present in the solvent. The above method comprising: determining the amount of by analysis.
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| US60/089,153 | 1998-06-12 | ||
| PCT/US1999/013241 WO1999064480A1 (en) | 1998-06-12 | 1999-06-10 | Novel ion exchange porous resins for solid phase extraction and chromatography |
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- 1999-06-10 AU AU44373/99A patent/AU4437399A/en not_active Abandoned
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2009215566A (en) * | 1998-06-12 | 2009-09-24 | Waters Investments Ltd | Novel ion exchange porous resin for solid phase extraction and chromatography |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1091981A1 (en) | 2001-04-18 |
| DE69936920T2 (en) | 2008-05-15 |
| US20060021939A1 (en) | 2006-02-02 |
| US20120248033A1 (en) | 2012-10-04 |
| US20090139323A1 (en) | 2009-06-04 |
| US20100324159A1 (en) | 2010-12-23 |
| EP1091981A4 (en) | 2003-04-02 |
| US8574433B2 (en) | 2013-11-05 |
| US7790038B2 (en) | 2010-09-07 |
| EP1091981B1 (en) | 2007-08-22 |
| JP2002517574A (en) | 2002-06-18 |
| WO1999064480A1 (en) | 1999-12-16 |
| US20100300972A1 (en) | 2010-12-02 |
| US7731844B2 (en) | 2010-06-08 |
| US7442299B2 (en) | 2008-10-28 |
| AU4437399A (en) | 1999-12-30 |
| US8197692B2 (en) | 2012-06-12 |
| US20070205156A1 (en) | 2007-09-06 |
| JP2009215566A (en) | 2009-09-24 |
| DE69936920D1 (en) | 2007-10-04 |
| US6322695B1 (en) | 2001-11-27 |
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